DESCRIPTION (Taken from the application): The dominantly inherited form of dystrophic epidermolysis bullosa (DDEB), a mechanobullous disease which presents with blister formation in the skin, is the result of dominant negative mutations in the type VII collagen gene (COL7Al). These mutations cause conformational changes in type VII collagen that interfere with the proper assembly of anchoring fibrils, important attachment structures of the cutaneous basement membrane zone. Currently, there is no available treatment option nor applicable in vitro experimental model for DDEB. The aim of the proposed research is to evaluate the feasibility of a novel treatment option, utilizing hammerhead ribozymes and deoxyribozymes for the targeted ablation of mutant COL7AI mRNA. Hammerhead ribozymes and deoxyribozymes targeting mutant COL7A1 mRNA will be designed, manufactured and tested utilizing already established methodology. We will engineer a three-dimensional skin model using human dermal fibroblasts and immortalized DDEB patient keratinocytes that will form a cutaneous basement membrane with the characteristics of DDEB. This model will serve as in vitro system to test the proposed novel treatment strategy for DDEB.